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Mechanism of interaction of niflumic acid with heterologously expressed kidney CLC-K chloride channels.

TitleMechanism of interaction of niflumic acid with heterologously expressed kidney CLC-K chloride channels.
Publication TypeJournal Article
Year of Publication2007
AuthorsPicollo A, Liantonio A, Babini E, Camerino DConte, Pusch M
JournalJ Membr Biol
Volume216
Issue2-3
Pagination73-82
Date Published2007 Apr
ISSN0022-2631
KeywordsAnimals, Chloride Channels, Drug Synergism, Flufenamic Acid, Humans, Kidney, Models, Biological, Niflumic Acid, Phenylpropionates, Rats, Xenopus laevis
Abstract

CLC-K Cl(-) channels belong to the CLC protein family. In kidney and inner ear, they are involved in transepithelial salt transport. Mutations in ClC-Kb lead to Bartter's syndrome, and mutations in the associated subunit barttin produce Bartter's syndrome and deafness. We have previously found that 3-phenyl-CPP blocks hClC-Ka and rClC-K1 from the extracellular side in the pore entrance. Recently, we have shown that niflumic acid (NFA), a nonsteroidal anti-inflammatory fenamate, produces biphasic behavior on human CLC-K channels that suggests the presence of two functionally different binding sites: an activating site and a blocking site. Here, we investigate in more detail the interaction of NFA on CLC-K channels. Mutants that altered block by 3-phenyl-2-(p-chlorophenoxy)propionic acid (CPP) had no effect on NFA block, indicating that the inhibition binding site of NFA is different from that of 3-phenyl-CPP and flufenamic acid. Moreover, NFA does not compete with extracellular Cl(-) ions, suggesting that the binding sites of NFA are not located deep in the pore. Differently from ClC-Ka, on the rat homologue ClC-K1, NFA has only an inhibitory effect. We developed a quantitative model to describe the complex action of NFA on ClC-Ka. The model predicts that ClC-Ka possesses two NFA binding sites: when only one site is occupied, NFA increases ClC-Ka currents, whereas the occupation of both binding sites leads to channel block.

DOI10.1007/s00232-007-9034-z
Alternate JournalJ. Membr. Biol.
PubMed ID17659402
Grant ListGGP04018 / / Telethon / Italy